CD36 is a multifunctional 88kD transmembrane glycoprotein expressed on platelets, monocytes, macrophages, certain specialized epithelial cells, and adipocytes. It has been shown to function as a cellular receptor for thrombospondin (TSP) and has recently been implicated as a macrophage scavenger receptor for oxidized low density lipoprotein (OxLDL). Oxidation of LDL is strongly linked to the pathogenesis of atherosclerosis in that lipid accumulation in atheromatous plaque results directly from internalization of OxLDL by intimal macrophages. In addition, OxLDL interactions with vascular cells may result in cellular activation to a prothrombotic, proatherogenic phenotype. The central hypothesis of this proposal is that CD36 is a major macrophage receptor for binding and internalizing ligands, including TSP and OxLDL. The focus will be to define the molecular basis of CD36 function and to probe its role in atherosclerosis. Studies in specific aim l will define structure-function relationships that govern CD36 receptor-ligand binding. Interactions with TSP and Oxidized LDL will be studies. These experiments will utilize recombinant CD36 peptides and solid phase and cellular binding studies. Specific aim 2 will define the mechanisms by which human macrophage CD36 internalizes ligands. Regulation of macrophage CD36 mRNA synthesis and surface protein expression in response to mediators of atherogenesis and differentiation will be studied using RNAse protection assays and immunomicroscopy. CD36-mediated internalization pathways and structure-function relationships that govern internalization will also be probed. Aim 3 will evaluate the role of CD36 in monocyte/macrophage biology by developing and studying a murine model genetically engineered so as not to express CD36. Completion of this project will increase understanding of early atherogenic events and allow for the development of novel therapeutic strategies by specific blockade of OxLDL-macrophage interactions. Furthermore, understanding how internalization and intracellular signaling is accomplished by CD36 may lead to broader insight into cellular function. The animal model may also be useful in testing the role of oxidants and anti-oxidants in atherogenesis.